Type of article- Original article
Title of Manuscript- Effect of Clonidine added to Caudal Ropivacaine in Pediatric Infraumbilical Surgeries
Running Title- Postoperative Analgesia in Children
ABSRACT:
Background and Aims: Caudal analgesia produces profound intraoperative as well as postoperative analgesia with minimal psychological alteration in children. Because of short duration, various additives have been used to prolong the duration of analgesia. The present study aimed to evaluate effect of addition of clonidine to ropivacaine in caudal analgesia for children undergoing infraumbilical surgeries.
Methods: We conducted a prospective, randomized, double blind study. After written informed consent from parents, 60 patients belonging to American Society of Anesthesiologist physical status I – II, in the age group 1-12 years, of either sex, undergoing infraumbilical surgery under general anesthesia were enrolled. Patients were randomized into two groups,
Group A: Control group- Ropivacaine 0.2% (1ml/kg)
Group B: Clonidine group- Ropivacaine 0.2% (1ml/kg) with clonidine 1µg/kg in normal saline with maximum volume 12 ml in both groups.
All patients were assessed intraoperative for hemodynamic changes and postoperatively for pain by using FLACC pain score and for sedation by using four point sedation score.
Results: The duration of analgesia was 707.3 + 59.56 minutes for group B and 411.83 + 14.82 minutes for group A. The first analgesic requirement time was statistically prolonged in group B as compared to group A (P < 0.05). Total analgesic consumption was statistically higher in group A (180+70 mg) when compared with group B (90+70 mg) (P < 0.05)
Conclusion: Addition of clonidine to ropivacaine in caudal analgesia significantly increases the duration of post-operative analgesia, without increasing the incidence of adverse effects.
Key words: Clonidine, caudal analgesia, children, infraumbilical surgeries, ropivacaine.
Introduction
Caudal epidural block is safe, reliable and easy method to administer and is therefore well accepted technique for intra-operative and post-operative analgesia especially for infraumbilical surgeries in young children. Due to short duration of analgesia even with the use of long-acting local anesthetics like bupivacaine and ropivacaine. [1] Various additives are required to prolong the duration of analgesia provided by single injection.
Ropivacaine, an amide local anesthetic, gives some advantages than bupivacaine. e.g., less cardiac and neurological toxicity, prolonged sensory analgesia and less motor blockage. [2] Addition of adjuvant (opioids, ketammine etc) prolongs the duration of block. Clonidine, an alpha 2 adrenergic agonist, prolongs analgesia without significant respiratory depression. The analgesic action of epidurally administered clonidine is due to stimulation of descending noradrenergic medullospinal pathways inhibiting the release of nociceptive neurotransmitters in the dorsal horn of spinal cord. [3]
We designed the present study using ropivacaine alone and ropivacaine with clonidine, in caudal epidural block in order to assess duration and efficacy of postoperative analgesia, degree of sedation, hemodynamic changes and any side effects.
Methods:
After obtaining proper written and informed consent from parents. This prospective, randomized, double blind study conducted in the pediatric surgical operation theater in civil hospital between August 2016 to December 2017 and total 60 patients of either sex, American Society of Anesthesiologist physical status I- II, age 1 to 12 years, weighing 5 to 30 kg, undergoing elective infraumbilical surgeries under general anesthesia. The patients having bleeding or coagulation test abnormalities, infection at the site of caudal block, congenital anomaly of the spine, pre-existing neurological disease or hypersensitivity of any local anesthetic of the amide type were excluded from the study. The patients included in the study were randomized before induction of anesthesia by using computer generated randomization numbers into two equal groups:
Group A: Control group- Ropivacaine 0.2% (1ml/kg)
Group B: Clonidine group- Ropivacaine 0.2% (1ml/kg) with clonidine 1µg/kg in normal saline with maximum volume 12 ml in both groups.
The anesthesiologist performing the caudal block was blinded about the drug preparation and patients.
Standard monitoring including ECG, NIBP, SpO2, EtCO2 were applied. An intravenous access was secured and glycopyrrolate inj. (0.004mg/kg) and ondensetron inj. (0.15mg/kg) were administered. Induction of anesthesia was achieved with sevoflurane (1-6%) and 50% nitrous oxide in oxygen or intravenous thiopental sodium 5-6mg/kg. In left lateral position caudal block was performed using 22-gauge Touhy epidural needle under complete aseptic precaution. The epidural space was localized and confirmed by loss of resistance to saline technique with 2 ml syringe, and the study drugs were administered into the caudal space slowly with continuous ECG monitoring. The patients were repositioned supine. To facilitate insertion of an I-gel or endotracheal tube intravenous succinylcholine 1-2 mg/kg was given. Intra-operative no analgesic was supplemented. During surgical procedure, anesthesia was maintained with assisted ventilation using sevoflurane (2-0.6%) or controlled ventilation using atracurium inj. (0.5 mg/kg) with 50% nitrous oxide in oxygen and sevoflurane (2-0.6%). Glucose/saline solution was infused as per requirement and peri-operative blood loss was replaced as per requirement.
During surgical procedure adequate analgesia was assessed by hemodynamic stability as indicated by the absence of an increase in heart rate or systolic blood pressure more than 15% compared with baseline values obtained just before the surgical incision. An increase in heart rate or systolic blood pressure more than 15% from baseline values within 20 minutes of skin incision indicated failure of caudal analgesia. At the end of surgery all the anesthetics gases were turned off and residual neuromuscular block was antagonized with neostigmine inj. 0.05 mg/kg and glycopyrrolate inj. 0.008 mg/kg intravenously. The patients were extubated in a fully conscious condition and during inspiration.
Intra-operatively concentration of sevoflurane was recorded every 15 minutes. Heart rate, NIBP, SpO2, EtCO2 and temperature were recorded every 15 minutes till the end of surgery. Duration of surgery, duration of anesthesia and peri-operative complications like brady/tachycardia, hypo/hypertension, respiratory depression, nausea, vomiting and urinary retention were recorded.
In the recovery room hemodynamic parameter, sedation and pain score were recorded at a 10 min interval after extubation and thereafter at interval of 1,2,4,6,8,10,12,15,18,21 and 24 hour. A four point sedation score was employed to assess the postoperative sedation [4] (0-spontaneous eye opening, 1-eye open on speech, 2-eye open on shake, 3-unarousable). Postoperative pain and duration of analgesia was evaluated by using FLACC score [5] (F= Face, L=Leg A= Activity, C= Cry, C=Consolability). The score 0 – no pain, 1 to 3 – mild pain, 4 to 7- moderate pain, 8 to 10 – severe pain and has maximum score of 10. Children who had a pain score of more than 4 were administered 15 mg/kg paracetamol intravenously. The total amount of the analgesic dose was recorded. All the patients were observed for next 24 h by a senior resident of anesthesiology. The patients were discharged the next day. During the follow-up after 1 week, none of the patients complained of any side effects or untoward incident.
In this study, sample size was calculated using formula n= 4pq/E2 which is based on Hardy-Weinbergg principle. In this formula p is the prevalence of infraumbilical pediatric surgery at civil hospital. 60 patients were allocated randomly into two equal groups (30 patients/group). Collected data were presented as mean ± SD and numbers as appropriate. Analysis of categorical variables was done by using chi-square with yate’s correction and Fisher’s exact test (two tailed) as appropriate. Continuous variables were analyzed using an unpaired student’s t-test. All statistical analysis was done by using Microsoft Office Excel 2010 and Graph Pad Prism 6.05 (quickcalc) Software. P value of less than 0.05 was considered statistically significant.
Results:
There was no statistically significant variation between two groups with regard to age, sex, weight, ASA grade and device used to secure an airway (Table 1). There was no statistically significant difference between two groups regarding the duration of surgery or time to extubation from cessation of anesthesia (P> 0.05) and SpO2 (>96%) was always within the clinically acceptable range in both the groups. There was no statistically significant variation between two groups regarding the types of surgery; majority of patients in both groups underwent hypospadias and hernia repair surgeries. (Table 2)
Table 3 shows that baseline heart rate recorded before the induction of general anesthesia was same in both the groups. Comparison with baseline value shows that heart rate decreased significantly in group B as compared to group A (P < 0.05). No patients in either had a drop in heart rate to <80 beats/min
There was no statistically significant difference between the two groups regarding the systolic blood pressure and post-operative complications such as vomiting, urinary retention and respiratory depression (P> 0.05). (Table 4, 5)
The duration of analgesia was 707.3 + 59.56 minutes for group B and 411.83 + 14.82 minutes for group A. The first analgesic requirement time was statistically prolonged in group B as compared to group A (P < 0.05). Total analgesic consumption was statistically higher in group A (180+70 mg) when compared with group B (90+70 mg) (P < 0.05) (Table 6). During postoperative period, requirement of paracetamol administration was once in seventeen patients and twice in 1 patient in group B as compared to once in twenty two patients and twice in seven patients in group A (P < 0.05). While twelve patients in group B and 1 patient in group A did not require additional paracetamol during the first 24 h study period, which was statistically significant (P < 0.05).
Mean hourly pain score in recovery room in both the groups were similar up to 4 hours after injection. Thereafter, the mean score in group A was significantly higher than that in group B (P < 0.05) (Figure1). No motor impairment was seen in either group on awakening and during the next 24 h period.
During first 30 minutes in recovery room sedation score was above 1 in group B while in group A, sedation score was below 1. Thereafter, sedation score in both the groups were similar during 24 hour (Figure2). There was no statistically significant difference between the two groups regarding post-operative sedation score (P> 0.05).
Discussion:
Postoperative analgesia provides not only pain relief but also inhibits trauma induced nociceptive impulses to blunt autonomic reflexes.
Enteral and parenteral analgesics (both opioids and non-opioids), used for providing postoperative analgesia, are associated with risks like gastro-intestinal bleeding, precipitation of asthma, nausea and vomiting, thrombocytopenia, sedation, respiratory depression, hepatotoxicity, nephrotoxicity etc. The regional techniques including the caudal block, avoid most of the problems and it is possible to achieve analgesia with minimum of drug dose and complications.
Caudal epidural block has been a popular technique to provide intraoperative and postoperative analgesia in children as it is easy to perform and safe.
Bupivacaine is the most commonly used local anesthetic in caudal analgesia but recently ropivacaine has proved to be more appropriate in pediatric age group due to its similarity in the duration of action to bupivacaine with the lesser motor blockade and less cardio toxicity. Brockway et al. [7] reported that ropivacaine produces slower onset with less intense motor blockade when compare to a similar concentration of bupivacaine.
Ropivacaine is being increasingly used even in pediatric age group in caudal route because of its less motor blockade and systemic toxicity. [8, 9]
Because of the short duration of single shot caudal blockade, various adjuvants are added to local anesthetic to prolong the duration of analgesia.
Clonidine is an alpha 2 adrenoceptor agonist, which was widely used as an antihypertensive in 70’s and 80’s, and presently it has been increasingly used for sedation, premedication, and as an adjuvant analgesic. It is also being used as an adjunct to local anesthetic in neuraxial block.[10] Several pediatric studies involving caudal use of clonidine together with local anesthetics have indicated a spinal mechanism of action.[11-13]
Klimscha et al had found that the addition of clonidine 1-2µg/kg to bupivacaine 0.25% significantly prolonged the mean duration of analgesia and reduced the total dose of postoperative analgesics compared with bupivacaine alone or bupivacaine plus epinephrine 52µg/ml (P< 0.05).[14]
Ivani G et al. [15] stated that 0.2% ropivacaine (2 mg/kg) is sufficient to obtain sensory block for lower abdominal or for genital surgery in children and ropivacaine produces a lesser postoperative motor blockade as compared to bupivacaine when used in a lower concentration.
Habre W et al [2] found that 1 ml/kg 0.25% ropivacaine by caudal route produces a maximal plasma concentration of 0.72±0.24 mg/lit, while Knudsen K et al [21] reported that i.v. infusion of ropivacaine produces the maximal tolerated plasma concentration in adult volunteers (2.2±0.8 mg/lit).
Therefore, in our study 0.2% 1 ml/kg ropivacaine has been chosen and no apparent motor deficit in our patients was seen probably due to the lower concentration of ropivacaine used.
We found that caudal ropivacaine alone provided excellent analgesia for 411.83 + 14.82 minutes after an operation, and rescue analgesics were required. With addition of clonidine postoperative analgesia was prolonged significantly up to 707.3 + 59.56 minutes.
Laha A et al. [6] reported that caudal block with addition of clonidine (2µg/kg) as an adjuvant with 0.2% ropivacaine increases the duration of postoperative analgesia without prolongation of motor blockade or production of any other side effects.
Balasubramanian S et al. [16] reported that addition of clonidine (1µg/kg) as an adjuvant to 0.1% ropivacaine for caudal analgesia significantly prolongs the duration of postoperative analgesia with minimal changes in hemodynamic parameters without any other side effects.
Bajwa SJ et al. [17] reported that caudal block using combination of 0.25% of isobaric ropivacaine 0.5 ml/kg with 2µg/kg of clonidine gives excellent analgesia intra-operatively as well as prolonged duration of analgesia post-operatively.
Luz et al. [18] found that using 0.1% ropivacaine in caudal anesthesia had shorter duration of analgesia when compared to 0.2% ropivacaine and 0.2% bupivacaine.
Clonidine causes dose-dependent postoperative sedation in children. [13] Some studies reported that addition of clonidine as an adjuvant to ropivacaine for caudal analgesia does not produce postoperative sedation significantly. [15, 17]
In our study, the post-operative sedation score was not statistically significant in the clonidine group after 30 minutes of post-operative period.
The undesirable side effects of neuraxial clonidine are hypotension and bradycardia. Though some studies in adult patients have reported a decrease in mean arterial pressure (MAP) and heart rate (HR) within 15-30 minutes after an epidural injection, which lasted for 3-4 hrs. before returning to baseline, others did not show any such hemodynamic alteration.[19,20]
Regarding HR, epidural clonidine caused bradycardia due to sympathetic predominance. In our study, we found that there was a statistically significant decrease in the HR for the group B as compared to group A (P value of <0.05). However, none of the children required drug intervention for decrease in HR as the hemodynamic parameters were not below the defined criteria.
Regarding the mean arterial blood pressure, epidural clonidine causes hypotension due to the inhibition of preganglionic sympathetic fibers. In our study, we found that there was no statistically significant fall in the systolic blood pressure (P value <0.05) in both the groups. However, none of the children required drug intervention for hypotension as the hemodynamic parameters were not below the defined criteria.
Conclusion: We conclude that addition of clonidine (1µg/kg) as an adjuvant with 0.2% ropivacaine through caudal route prolongs the duration of post-operative analgesia in children undergoing infraumbilical surgeries, without increasing the incidence of adverse effects.
References:
1. Verghese ST, Hannallah RS. Postoperative pain management in children. Anesthesia Clin North America 2005; 23:163–84.
2. Habre W, Bergesio R, Johnson C, Hackett P, Joyce D, Sims C et al. Pharmacokinetics of ropivacaine following caudal analgesia in children. Pediatric Anesth 2000; 10:143–7.
3. Cook B, Dayle E. The use of additives to local anesthetic solutions for caudal epidural blockade. Pediatric Anesth 1996; 6:353–9.
4. Ho D, Keneally JP. Analgesia following pediatric day-surgical orchidopexy and herniotomy. Pediatric Anesth 2000; 10:627-31.
5. Merkel SI, Voepel-Lewis T, Shayevitz JR, Malviya S. The FLACC: a behavioral scale for scoring postoperative pain in young children. Pediatric Nurs 1997; 23:293–7.
6. Laha A, Ghosh S, Das H. Comparison of caudal analgesia between ropivacaine and ropivacaine with clonidine in children: A randomized controlled trial. Saudi Journal of Anesthesia 2012; 6:197-200.
7. Brockway MS, Bannister J, McClure JH, McKeown D, Wildsmith JA. Comparison of extradural ropivacaine and bupivacaine. Br J Anesth 1991; 66:31-7.
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10. Lonnqvist PA. Adjuncts to caudal block in children-Quovadis? Br J Anesth 2005; 95:431-3.
11. Nishina K, Mikawa K, Shiga M, Obara H. Clonidine in pediatric anesthesia. Pediatric Anesth 1999; 9:187-202.
12. Jamali S, Monin S, Begon C, Dubousset AM, Ecoffey C. Clonidine in pediatric caudal anesthesia Anesth Analg 1994; 78: 663-6.
13. Lee JJ, Rubin AP. Comparison of a bupivacaine clonidine mixture with plain bupivacaine for caudal analgesia in children. Br J Anesth 1994; 72: 258-62.
14. Klimscha W, Chiari A, Michalek-Sauberer A, Wildling E, Lerche A, Lorber C, et al. The efficacy and safety of clonidine/bupivacaine combination in caudal blockade for pediatric hernia repair. Anesth Analg 1998; 86:54-61.
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Table 1: Demographic data in both
Patient characteristics Group A
(N=30) Group B
(N=30) P Values
Age (years) 3.00 + 1.58 3.24 + 1.61 0.5623
Weight (kg) 11.07 + 0.65 11.00 + 0.53 0.6493
Sex (M:F) 29:1 29:1 1.000
ASA Grade I/II 26/4 27/3 1.000
Duration of Surgery(hr.) 1.32±0.65 1.28±0.67 0.8153
I-gel/ ET Tube Insertion 18/12 19/11 1.000
Time to extubation (Min) 4.32±1.65 4.58±1.76 0.5573
Postoperative SpO2 97±2.56 96±2.86 0.1590
*ASA-American Society of Anesthesiologist
Data presented as mean ± SD or Number: *P value < 0.05 is considered significant
Table 2: Types of Surgery
Surgical procedure Group A
(N=30) Group B
(N=30) P Value
Inguinal hernia 5 7 0.7480
Hypospadias 20 16 0.4296
Orchidopexy 2 4 0.6707
Cystolithotomy 3 3 1.0000
Data presented as Number: *P value < 0.05 is considered significant
Table 3: Comparison of Pulse Rate per minute
Duration (Time) Group A
(N=30) Group B
(N=30) P Values
Basal 128.3 ± 14.22 127.1.7 ± 9.50 0.7187
5 min after caudal 134.7± 11.60 130.1 ± 9.50 0.0983
10 min 123.9± 11.63 112.3 ± 9.05 <0.0001*
20 min 120.2± 11.47 104.4 ± 9.82 <0.0001*
30 min 118.5± 11.87 91.4 ± 10.36 <0.0001*
40 min 112.97 ± 13.26 94.25 ± 7.87 <0.0001*
50 min 113.3 ± 12.69 99.5 ± 9.65 <0.0001*
60 min 112.3 ± 8.92 103.3 ± 11.94 0.0016*
70 min 113.4 ± 10.06 100.5 ± 10.51 <0.0001*
80 min 114.6 ± 8.70 102.2 ± 12.00 <0.0001*
90 min 128±28.23 103.6±7.97 <0.0001*
Data presented as mean ± SD or Number: *P value < 0.05 is considered significant
Table 4: Comparison of Systolic blood pressure (mm of Hg)
Time Group A
(N=30) Group B
(N=30) P Values
Basal 107.03±3.27 105.03±5.94 0.1116
5 min after caudal 105.05±4.37 103.07±6.04 0.1511
10 min 94.37±7.14 92.4±4.19 0.1976
20 min 91.07±6.90 89.1±5.03 0.2114
30 min 90.37±7.80 88.4±5.39 0.2598
40 min 91.03±11.63 88.43±6.21 0.2845
50 min 92.9±12.14 88.73±7.49 0.1148
60 min 93.33±11.97 90.6±8.36 0.3100
70 min 97.1±9.44 94.37±7.55 0.2211
80 min 97.73±7.95 94.33±8.43 0.1135
90 min 98.13±8.95 95.63±8.69 0.2769
Data presented as mean ± SD or Number: *P value < 0.05 is considered significant
Table 5: Postoperative complications
Sr. No. Complications Group A Group B P value
1 Vomiting 1 2 1.0000
2 Urinary retention 0 0 1.0000
3 Respiratory depression 0 0 1.0000
4 Miscellaneous 0 0 1.0000
Data presented as Number: *P value < 0.05 is considered significant
Table 6: Drug Characteristics in both the groups
Characteristics Group A Group B P Value
Mean duration of analgesia(minutes) 411.83 + 14.82 707.3 + 59.56 <0.0001*
Total analgesic dose (mg) 180+70 90+70 <0.0001*
Data presented as mean ± SD or Number: *P value < 0.05 is considered significant
Legends for Illustrations:
Figure 1 Post-operative pain score (FLACC Score) during first 24 hours in both groups. The difference was statistically significant at 4, 6, and 8 hours after surgery. ( Shows P value < 0.05). Data presented as mean.
Figure 2 Post-operative sedation score (four point sedation score) during first 24 hours in both groups. Group B had sedation score above 1 in immediate postoperative period as compared to Group A. ( shows P value < 0.05). Data presented as mean